Alkylsulfinylalkyl- and sulfonyl-
alkyl-i,z,j,x.tetrahydroisoqijinolines

ABSTRACT

N-SUBSTITUTED 1,2,3,4-TETRAHYDROISOQUINOLINES EXEMPLIFIED BY 2-(3-ETHYLSULFINYLPROPYL)- 1,2,3,4-TETRAHYDROISOQUINOLINE.   2-(CH3-CH2-SO-(CH2)3-)-1,2,3,4-TETRAHYDROISOQUINOLINE   EXERT CARDIOVASCULAR EFFECTS WHEN ADMINISTERED AS THEIR HYDROCHLORIDES. SUCH SULFINYL COMPOUNDS ARE PREPARED BY OXIDATION OF THE CORRESPONDING THIO ETHERS, WHICH MAY ALSO BE OXIDIZED TO THE CORRESPONDING SULFONYL COMPOUNDS. SUBSTITUTION ON THE AROMATIC AND HETEROCYCLIC RINGS AND VARIATIONS IN THE CHAIN ARE DISCLOSED.

United States Patent Ofice Re. 28,034 Reisaued June 4, 1974 28,034 N-ALKYISULFINYLALKYL- AND SULFONYL- ALKYL-1,2,3,4-TETRAHYDROISOQUINOLINES Allan Poe Gray, Essex Junction, Vt, assignor to Mallincltrodt Chemical Works, St. Louis, M0.

N Drawing. Original No. 3,549,640, dated Dec. 22, 1970, Ser. No. 680,354, Nov. 3, 1967. Application for reissue Dec. 14, 1972, Ser. No. 314,968

Int. Cl. C07d 35/42 US. Cl. 260-283 S 8 Claims Matter enclosed in heavy brackets [II appears in the original patent but forms no part of this reissue specification; matter printed in italics indicates the additions made by reissue.

ABSTRACT OF THE DISCLOSURE -N-substituted 1,2,3,4 tetrahydroisoquinolines exemplified by 2-(3-ethylsulfinylpropyl) l,2,3,4 tetrahydroisoquinoline.

exert cardiovascular eiiects when administered as their hydrochlorides. Such sulfinyl compounds are prepared by oxidation of the corresponding thio ethers, which may also be oxidized to the corresponding sulfonyl compounds. Substitution on the aromatic and heteroeyclic rings and variations in the side chain are disclosed.

This invention relates to compositions of matter classified in the art of chemistry as tetrahydroisoquinolines having an aliphatic sulfur-containing substitutent attached to the ring nitrogen atom.

The invention sought to be patented in its composition aspect, is described as residing in the concept of a chemical compound having the generalized structure:

N-A-X-R wherein A contains up to 7 carbon atoms and is selected from the group consisting of alkylene; alkenylene; alkyleneoxycarbonyl; or alkyleneamino; X is selected from the group consisting of thio, sulfinyl or sulfonyl; R contains up to 7 carbon atoms and is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, alkaryl, arakyl, amino, aminoalkly, alkyiamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, amidino, aminothiocarbonyl, alkylthiocarbonyl, cyano or akylsulfonyl; R represents a member selected from the group consisting of hydrogen or alkyl; and R" represents a member selected from the group consisting of lower alkyl, lower alkoxy, aminoalkyl, lower dialkylamino, acetamino, halo, e.g., chloro, bromo, fluoro, iodo; haloalkyl, e.g., chloromethyl, trifiuoromethyl; or methylenedioxy, i.e. two

R"s form -0Ci-I,O wherein the oxygen atoms are attached to the aromatic ring at adjacent positions, and n has a value of from zero to 2.

As used herein, the term lower alkyl" means alkyl radicals having 1 to 4 carbon atoms, inclusive, either straight or branched chain, among which are, for purposes of illustration, but without limiting the generality of the foregoing, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, secondary-butyl, and tertiary-butyl.

Preferred compositions encompassed by this invention are those represented by the aforementioned formula wherein A contains from 2 to 6 carbon atoms and R, R and *R" each contain up to 7 carbon atoms. Also preferred compositions are those wherein R and R" represents hydrogen, X represents thio, sulfinyl, or sulfonyl, A represents an alkylene group and R represents alkyl. Particularly preferred compositions are those wherein the ring nitrogen and the sulfur atoms are separated by at least 3 carbon atoms, i.e. A has at least 3 unbranched carbon atoms, and the total number of carbon atoms in A and R is from 5 to 7.

The invention sought to be patented in the process of preparation aspects is described as residing in the concept of embodying such a molecular structure in tangible form by linking a sulfur-containing organic moiety and a tetrahydroisoquinoline through its nitrogen atom by one or more processes. For example the compositions can be formed by (1) the reaction of a 2-(haloalkyl)-l,2,3,4- tetrahydroisoquinoline with thiol to give a 2-(thioa1kyl)- l,2,3,4-tetrahydroisoquinoline (2) oxidizing the 2-(thi0- alkyl)-1,2,3,4 tetrahydroisoquinoline to a 2 (sulfinylalkyl)-l,2,3,4-tetrahydroisoquinoline, or (3) oxidizing the 2-(thioalkyl)-1,2,3,4 tetrahydroisoquinoline to the corresponding 2-(sulfonylalkyl-l,2,3,4 tetrahydroisoquinoline.

The invention sought to be patented, in the process of using aspect, is described as residing in the concept of using the tangible embodiment of a composition of matter identified as a tetrahydroisoquinoline with a sulfur-containing substituent on the nitrogen atom by administering to warm blooded animals such composition as the essential active ingredient of a pharmaceutical formulation. It has been observed that the tangible embodiments of the invention possess the inherent applied use characteristics of increasing blood pressure and producing favorable cardiovascular effects as hereinafter evidenced by clinical evaluation. In addition to increasing blood pressure, the novel compositions of this invention have also been found to have vasodilator activity.

The tangible embodiments of the composition aspect of the invention in their free base form are, for the most part, liquids having low aqueous solubility and are soluble in polar solvents such as lower aliphatic alcohols. Examination of the compounds produced according to the herein described process reveals physical characteristics such as infrared spectra which confirm the molecular structure hereinbefore set forth. The aforementioned physical characteristics, taken together with analytical data the nature of the starting materials and the mode of synthesis positively confirm the structure of the compositions sought to be patented.

It will be apparent from the definition of A-X-R in the aforementioned formula that it is intended to include specifically or as equivalents, such representative radicals as the thioalkyl groups, e.g., methylthiomethyl, methylth opropyl, ethylthiopropyl, propylthiopropyl, methylthioisopropyl, butylthiopropyl, cyclohexylthiopropylthiopropyl, methylaminoethylthiopropyl, dimethylaminopropylthiopropyl, diethylaminopropylthiopropyl, and the like; the amidinothioalkyl grous, e.g., amidinothiopropyl, amidinothiobutyl, and the like; the the thiocyanoalkyl groups, e.g., thiocyanoethyl, thiocyanopropyl, thiocyanobutyl, thiocyanopentyl, thiocyanoisobutyl, and the like.

Further representative radicals included within the aforementioned formula are thioformoxyalkyl groups, e.g., ethylthioformoxyethyl, propylthioformoxyethyl, propylthioformoxypropyl, benzylthioformoxybutyl, benzylthioformoxypentyl, and the like: the thiocarbamylthioalkyl groups, e.g., thiocarhamylthioethyl, thiocarbamylthiopropyl, thiocarbamylthioisobutyl, and the like; the alkyycarbonyldithioalkyl groups, e.g., ethylcarbonyldithioethyl, and the like; the alkylsulfonylthioalkyl, e.g., ethylsulfonylthioethyl, and the like.

Additional representative radicals include the alkylsulfinylalkyl groups, e.g., ethylsulfinylpropyl, propylsulfinylpropyl, methylsulfinylethyl, propylsufinylethyl, and the like.

Further representative groups include the alkylsulfonylalkyl groups, e.g., ethylsulfonylpropyl, propylsulfonylpropyl, methylsulfonylethyl, and the like. Also included are the sulfamido groups, e.g., sulfamidoethyl, sulfamidopropyl, and the like; the dialkylsulfamidoalkyl, e.g., N,N-dimethylsulfamidoethyl, and the like.

Synthesis of the novel tetrahydroisoquinolines of the present invention may be efiected by a variety of processes as hereinafter indicated in the examples. For instance, the 2 (alkylthioalkyl) 1,2,3,4 tetrahydroisoquinolines are prepared by refluxing the appropriate alkylthionalkyl halide with tetrahydroisoquinoline. Alternatively, a 2-(haloalkyl)-tetrahydroisoquinoline hydrochloride can be prepared and then reacted with the appropriate alkylthiol in the presence of an acid acceptor. The sulfinyl and sulfonyl derivatives are prepared by oxidation of the corresponding thio compound. The generalized processes for the preparation of the thio comopsitions can be illusrtated as follows:

wherein A, n, R, R and R" are as previously defined and Y represents halogen, e.g., chloro, bromo, iodo, or R' -S wherein R'" is lower alkyl or aryl.

Thereafter, the thio composition (I) is oxidized to the corresponding sulfinyl or sulfonyl derivative.

In the above described synthesis, it will be apparent to those skilled in the art of chemistry that the proportion of reactants, duration of reaction, solvents, acid acceptors, catalysts and the like can be varied depending on the type of reactant.

From the specific reaction conditions given in the examples, it will be obvious to those skilled in the art of chemistry that the reagents and conditions which can be employed in the inventive process will depend to a great extent on the nature of the thiol as well as the particular tetrahydroisoquinoline.

In general, a temperature range from about 0' C. to about the reflux temperature of the solvent has been found to be satisfactory. Temperatures above and below the aforementioned range can also be employed but are less preferred. A preferred range is from about 25 C. to about 150 C.

It is also preferred, although not necessary, that the reaction of the tetrahydroisoquinoline and thio compound be conducted in an inert solvent. In general, the choice of solvent will largely be dependent upon its inability to undergo reactions with either the starting materials or reaction products, its ease of separation from the reaction product, as well as economic considerations.

A variety of inert solvents can be employed in the practice of the instant process, i.e., saturated aliphatic hydrocarbons, aromatic hydrocarbons, aliphatic alcohols, and the like. Typical solvents which can be employed include benzene, toluene, xylene, ethanol, tertiary butanol, secondary butanol, 2-propanol, tertiary amyl alcohol, methyl isobutyl carbinol, acetone, acetonitrile, dimethylformamide, and the like. Preferred solvents are those completely miscible with the reactants and which can be readily separated.

Pressure is not necessarily critical and the process can be conducted at atmospheric, subatmospheric or superatmospheric pressures.

The contact time necessary to effect the novel process of the present invention need only be of such duration as to insure optimum conversion of the reactants to the corresponding 2-substituted tetrahydroisoquinoline compound. Reaction times of several hours are thoroughly practicable. Shorter or longer periods can also be feasibly employed depending upon the temperature (higher temperatures usually permit the use of shorter reaction times), and the manner in which the process is conducted.

Oxidation of the Z-(aliphaticthioalkyl)-l,2,3,4-tetrahydroisoquinoline to the corresponding sulfinyl or sulfonyl compounds can be conveniently effected by known prior art procedures. For example, 2-(3-ethylthiopropyl)-l,2, 3,4-tetrahydroisoquinoline can be oxidized easily to 2-(3- ethylsulfinylpropyl) l,2,3,4 tetrahydroisoquinoline with peracetic acid. Other peroxides can also be employed.

Preparation of the 2-(alkylsulfonylalkyl)-l,2,3,4-tetrahydroisoquinolines are likewise prepared by the oxidation of the 2-(alkylthioalkyl)-1,2,3,4-tetrahydroisoquinolines with an appropriate oxidizing agent such as hydrogen peroxide and the like.

As previously indicated, the starting materials for the preparation of the novel composition of this invention are the tetrahydroisoquinolines and the thiols. These reactants are known compounds or can be prepared by the methods indicated in the examples.

The manner of making and using the compositions and processes of the invention is further illustrated by the following examples, which set forth one mode contemplated for carrying out the invention so as to enable any person skilled in the art of chemistry to make and use the same.

EXAMPLE 1 2-(3-methylthiopropyl)-l,2,3,4-tetrahydroisoquinoline A solution of 16.2 g. (0.13 mole) of 3-methylthiopropyl chloride and 34.6 g. (0.26 mole) of tetrahydroisoquinoline in 100 ml. of benzene was heated at reflux on a steam bath for hours during which a crystalline precipitate slowly formed. The precipitate was filtered off (tetrahydroisoquinoline hydrochloride, 14.7 g., 67% yield) and the fil- Cl(ionic), 13.78.

EXAMPLE 2 2-(3-ethylthiopropyl)-1,2,3,4-tetrahydroisoquinoline (A) A solution of 215 g. (1.6 moles) tetrahydroisoqninoline and 126 g. (0.8 mole) of trimethylene chlorobromide in 1300 ml. of benzene was stirred at room temperature for 100 hours. The precipitate of 130 g. of tetrahydroisoquinoline hydrobromide was filtered off and the filtrate was extracted with dilute hydrochloric acid. The aqueous extract was made alkaline with solid potassium carbonate and the precipitated oil taken into ether. Drying and removal of the ether and distillation of the residue yielded 89 g. (53%) of 2-(3-chloropropyl)-tetrahydroisoquinoline, B.P. 13l-137 (3 mm), n 1.5463.

Analysis.-Calcd. for C H ClN (percent): N, 6.68. Found (percent): N(basic), 6.63.

2-(3-chloropropyl)-tetrahydroisoquinoline hydrochloride, prepared in ether and recrystallized from isopropyl alcohol-ether, showed M.P. 187-187.5.

Analysis.Calcd. for c l-l Cl N (percent): C, 58.54; H, 6.96; Cl(ionic), 14.40. Found (percent): Cr, 58.27; H, 7.21; Cl(ionic), 14.40.

(B) To a cooled solution of 18.7 g. (0.81 g. atom) of metallic sodium in 300 ml. of ethanol was added 29.9 g. (0.48 mole) of ethanethiol. The solution was allowed to come to room temperature and 79.3 g. (0.32 mole) of 2-(3-chloropropyl)-tetrahydroisoquinoline hydrochloride dissolved in 150 ml. of methanol was added dropwise with stirring over a period of 20 minutes. A white precipitate formed during the addition. The reaction mixture was stirred at room temperature for 0.5 hour and at reflux for one hour. About 100 ml. of solvent was distilled out of the reaction mixture which was then poured into one liter of water and extracted with ether. The ether solution was extracted with dilute hydrochloric acid. A hydrochloride salt precipitate formed during the extraction. The aqueous mixture was made alkaline and extracted with ether. Drying and removal of the ether and distillation of the residual oil gave 61.5 g. (81%) of Z-(B-ethyl-thiopropyl) 1,2,3,4 tetrahydroisoquinoline, B.P. 150-156 (0.4 mm.), 11 1.5521.

Analysis.-Calcd. for C H NS (percent): N, 5.95. Found (percent): N(basic), 5.87.

2-(3-ethylthiopropyl) 1,2,3,4 tetrahydroisoquinoline hydrochloride, recrystallized from isopropyl alcohol, formed colorless plates, M.P. 2005-202.

Analysis.Calcd. for C H ClNS (percent): C, 62.02; H, 8.24; Cl, 13.04. Found (percent): C, 61.85; H, 8.16; Cl(ionic), 13.00.

EXAMPLE 3 2- (3-ethylsulfinylpropyl) 1,2,3 ,4-tetrahydroisoquinoline To an ice cold solution of 23.5 g. (0.1 mole) of the base produced in Example 2B and 6 ml. of glacial acetic acid in 50 ml. of acetonitrile was added, dropwise with stirring, a solution of 19 g. of commercial 40% peracetic acid (0.1 mole) in 25 ml. of acetonitrile. The reaction mixture was stirred at room temperature for a period of one hour, poured into 150 ml. of water, made basic with dilute aqueous ammonia and extracted with ether. The ether solution was washed with a dilute potassium carbonate solution, water, dried and treated with ethereal hydrogen chloride. The resultant precipitate was recrystallized from isopropyl alcohol to yield 13.4 g. (47%) of 2-(3-ethylsulfinylpropyl) l,2,3,4 tetrahydroisoquinoline hydrochloride in the form of colorless plates, M.P. 198- 199.

Analysis.Calcd. for C H CINOS (percent): C, 58.41; H, 7.70; Cl, 12.32. Found (percent): C, 58.53; H, 7.66; Cl(ionic), 12.35.

EXAMPLE 4 2- 3-ethylsulfonylpropy])-1,2,3,4-tetrahydro isoquinoline To a solution of 23.5 g. (0.1 mole) of the base produced in Example 28 in ml. of glacial acetic acid was added, dropwise with stirring and maintenance of the temperature at about 30 by external cooling, 27.2 g. of 50% hydrogen peroxide (0.4 mole). After the addition was complete, the solution was allowed to stand for 48 hours at room temperature, poured into 400 ml. of water, made basic and extracted with ether. The ether extract was shaken with dilute hydrochloric acid, the aqueous acid solution was made basic and extracted with ether. The ether layer was washed with water, dried over magnesium sulfate and treated with ethereal hydrogen chloride. Recrystallization of the precipitate from a mixture of isopropyl alcohol and ethanol afforded 13.6 g. (45%) of 2-(3-ethylsulfonylpropyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride in the form of colorless plates, M.P. 226-228.

Analysis.-Calcd. for C H CINO S (percent): C, 55.34; H, 7.30; Cl, 11.67. Found (percent): C, 55.13; H, 7.15; Cl(ionic), 11.78.

EXAMPLE 5 2- (3 -propylthiopropyl) 1,2, 3 ,4-tetrahydroisoquinoline To a stirred, ice cold solution of 16.1 g. 0.7 g. atom) of metallic sodium in 250 ml. of ethanol was added 31.2 g. (0.41 mole) of l-propanethiol. The solution was allowed to come to room temperature and a solution of 67.5 g. (0.27 mole) of the hydrochloride salt prepared in Example 28 in ml. of methanol was added dropwise with stirring. Stirring was continued and the reaction mixture was heated at reflux on a steam bath for 2.5 hours. The reaction mixture was concentrated to about one-half its original volume, poured into 700 ml. of water and extracted with ether. The ether solution was extracted with dilute hydrochloric acid. The aqueous acid solution was made basic with aqueous sodium hydroxide and extracted with ether. The ether was dried and evaporated and the residual oil distilled to give 60.1 g. (90%) of 2-(3-propylthiopropyl)-1,2,3,4-tetrahydroisoquinoline, B.P. -167 (0.2 mm.).

Analysis.-Calcd. for C H NS (percent): N, 5.62. Found (percent): N(basic), 5.67.

2-(3-propylthiopropyl) 1,2,3,4 tetrahydroisoquinoline hydrochloride, recrystallized from isopropyl alcoholether, formed colorless plates, M.P. 197.

Analysis.-Calcd. for C H CINS (percent): C, 63.02; H, 8.46; Cl, 12.40. Found (percent): C, 62.79; H, 8.49; Cl(Schiiniger), 12.51.

EXAMPLES 6-12 In the following examples the analogous compounds were prepared as indicated. The methods employed were the same as those set forth for the preceding examples. The physical constants and other analytical data are set forth in Table I:

at room temperature followed by 0.5 hour at reflux. The precipitate of triethylamine hydrochloride (9.0 g., 94%) was filtered off. Extraction of the filtrate with dilute hydrochloric acid precipitated the crude hydrochloride salt of the product which was recrystallized from acetonitrileether to give 7.1 g. (36%) (a small amount of additional material was obtained from the aqueous acid mother liquor) of 2 (ethylthiolformoxyethyl) l,2,3,4 tetrahydroisoquinoline hydrochloride, M.P. 174-176.

Analysis.Calcd. for CmHzoClNOzS (percent): C, 55.71; H, 6.68; Cl, 11.75. Found (percent): C, 55.86; H, 6.62; Cl(Schbnige), 11.85.

EXAMPLE 17 1,2,3 ,4-tetrahydroisoquinolinoethyl -isothiuronium chloride hydrochloride A mixture of 23.2 g. (0.1 mole) of Z-chloroethyltetrahydroisoquinoline hydrochloride, 15.2 g. (0.2 mole) of thiourea and 75 ml. of isopropyl alcohol was heated at reflux on a steam bath for 30 hours. The precipitate was collected and recrystallized from a mixture of isopropyl alcohol and methanol to give 24.3 g. (79%) of (1,23,4- tetrahydroisoquinolinoethyl)-isothiuronium chloride hydrochloride, M.P. 188-189.

Analysis.(2alcd. for C H Cl N S (percent): C, 46.75; H, 6.21; C], 23.00. Found (percent): C, 46.84; H, 6.57; Cl(ionic), 22.93.

EXAMPLE 18 2-(thiocarbamylthioethyl)-1,2,3,4-tetrahydroisoquinoline A solution of 20.3 g. (0.08 mole) of the hydrochloride salt of the product obtained in Example in 500 ml. of methanol was saturated with hydrogen sulfide at room temperature and allowed to stand for 36 hours. The reaction mixture was concentrated to dryness and the solid residue was taken up in water, made basic with aqueous ammonia and extracted with ether. The ether solution was dried over magnesium sulfate, treated with ethereal hydrogen chloride, and the precipitate was recrystallized from methanolether to yield 12.0 g. (52%) of 2-(thiocarbamylthioethyl) l,2,3,4 tetrahydroisoquinoline hydrochloride in the form of colorless prisms, M.P. 195- 196.

A nalysis.Calcd. for CmHflClNgSg (percent): S, 22.20 Cl, 12.27. Found (percent): S(Sch6niger), 22.69; Cl(Schbniger), 12.37.

EXAMPLE 19 1,2,3,4-tetrahydroisoquinolinoethyl ethanethiosulfonate A mixture of 28.9 g. (0.176 mole) of potassium ethanethiosulfonate, the base obtained from 53 g. (0.23 mole) of 2- chloroethyltetrahydroisoquinoline hydrochloride, 300 ml. of acetone and 20 ml. of water was stirred at room temperature for one hour and at reflux on a steam bath for five hours. The reaction mixture was filtered and the filtrate was concentrated to about one-third its volume and poured into 400 ml. of water. The oil precipitate was taken into ether. The ether extract was shaken with dilute hydrochloric acid, and the precipitate that formed was crystallized from methanol-ether to yield 2.9 g. of 1,2,3,4- tetrahydroisoquinolinoethyl ethanethiosulfonate hydrochloride as colorless platelets, M.P. 199-200.

Analysis.-Calcd. for C H CINO S (percent): S, 19.93; C1, 11.01. Found (percent): S(Sch6niger), 20.12; Cl(ionic), 11.38.

EXAMPLE 20 2-(ethylcarbonyldithioethyl) -1-1,2,3,4-tetrahydroisoquinoline (A) A slurry of 122 g. (0.396 mole) of the product obtained in Example 17 with 34 g. (0.85 mole) of sodium hydroxide in 300 ml. of water was saturated with sodium chloride and extracted with ether. The ether solution was dried and concentrated to leave a clear oil which was 10 distilled to yield 33.3 g. (43.5%) of 2-rnercaptoethyltetrahydroisoquinoline, B.P. (0.2 mm), n 1.5780.

Analysis.Calcd. for C H NS (percent): N, 7.25. Found (percent): N(basic), 7.20.

2 mercaptoethyl l,2,3,4 tetrahydroisoquinoline hydrochloride formed colorless needles from ethanol, M.P. 218-220".

Analysis.Calcd. for C I-I ClNS (percent): Cl, 15.43; S, 13.95. Found (percent): Cl(Schoniger), 15.86; S(Schiiniger), 13.90.

(B) A solution of 14.5 g. (0.064 mole) of the hydro chloride salt obtained in Example 20A and 5.1 g. (0.13 mole) of sodium hydroxide in ml. of water was washed with ether and treated with 8.7 g. (0.07 mole) of ethyl chlorothiolformate. A light yellow oil precipitate formed rapidly. After being stirred at room temperature for 1.5 hours, the reaction mixture was extracted with ether. The ether solution was shaken with dilute hydrochloric acid to precipitate a white solid which was recrystallized from acetonitrile-ether to yield 9.8 g. (48%) of 2 (ethylcarbonyldithioethyl) 1,2,3,4 tetrahydroisoquinoline hydrochloride, M.P. 161.6162.4.

Ana!ysis.Calcd. for C H CINOS (percent): C, 52.89; H, 6.34; Cl, 11.15; S, 20.17. Found (percent): C, 52.88; H, 6.58; Cl(Schoniger), 10.96; S(Sch6niger), 20.44.

EXAMPLE 21 2-sulfamidoethyl-1,2,3,4tetrahydroisoquinoline A mixture of 8.8 g. (0.05 mole) of 2-aminoethyltetrahydroisoquinoline, 4.8 g. (0.05 mole) of sulfamide and 5 ml. of water was heated at an oil bath temperature of 120 for 4.5 hours at which time ammonia evolution ceased. The reaction mixture was extracted with chloroform and the chloroform extract was dried and concentrated to an amber oil. An isopropyl alcohol solution of the oil was treated with ethereal hydrogen chloride and the precipitate was recrystallized from a mixture of methanol, ethanol and ether to yield 5.0 g. (40%) of 2-sulfarnidoethyl-l,2,3 ,4 tetrahydroisoquinoline hydrochloride as colorless plates, M.P. 186-187.

Analysis.Calcd. for C I-I ClN O S (percent): C, 45.28; H, 6.22; Cl, 12.15; S, 10.97. Found (percent): C, 45.82; H, 6.17; Cl(ionic), 12.27; S(Sch6niger), 10.81.

EXAMPLE 22 Z-dimethylsulfamidoethyl)-1,2, 3,4-tetrahydroisoquinoline To a solution of 7.9 g. (0.055 mole) of dimethylsulfarnyl chloride in 100 ml. of anhydrous ether was added, dropwise with stirring at room temperature, 8.8 g. (0.05 mole) of Z-aminoethyltetrahydroisoquinoline as a white precipitate began to form. The reaction mixture was stirred at room temperature for 20 hours and then at reflux for 7 hours. The precipitate of Z-aminoethyltetrahydroisoquinoline monohydrochloride was filtered off and the filtrate was concentrated to dryness. The residue was heated on a steam bath for 15 minutes, taken up in water and the aqueous solution was washed with ether, made basic and extracted with ether. Treatment of the dried ether extract with ethereal hydrogen chloride and repeated recrystallization of the precipitate from isopropyl alcohol afforded 4.0 g. (25%) of Z-dimethylsulfamidoethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride in the form of large colorless plates, M.P. -171".

Analysis.-Calcd. for C H CIN O S: (percent): C, 48.81; H, 6.93; Cl, 11.08. Found (percent): C, 48.82; H, 6.72; Cl(ionic), 11.08.

EXAMPLE 23 2-(3-ethylsulfonylpropyl)-6-methy1-1,2,3,4- tetrahydroisoquinoline In a manner similar to that set forth in Example 2A 2 (3-chloropropyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline is prepared from the reaction of G-methyltetrahydroisoquinoline (1.6 moles) and trimethylene chlorobromide 1 1 (0.8 mole), thereafter the hydrochloride salt is formed, recrystallized and dissolved in methanol. To a cooled solution of 18.7 grams (0.81 g. atom) of metallic sodium in 300 ml. of ethanol is adde 29.9 gram (0.48 mole) of ethanethiol. The solution is allowed to reach room temperature and the 2-(chloropropyl)-6-methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride (0.32 mole) dissolved in methanol is added dropwise. Thereafter the reaction mixture is stirred at reflux for about one hour. After distilltechnique with the pressure recored on a Beckman Continuous Systolic Monitor. Systolic and diastolic pressures of three dogs were also obtained with the electrosphygmograph cuff attachment to the physiograph, utilizing pressures from both the brachial and tail arteries.

Cardiac output was obtained by the dye-dilution method utilizing Cardio-Green dye and a Waters Densitometer. Dye injections were made through a catheter inserted through the right jugular vein and positioned ing off a portion of the solvent, the reaction mixture is near, or in the right atrium. Arterial sample for dye was poured into water and extracted with ether. The ether from the left carotid artery. solution is then extracted with dilute HCl, the aqueous The Shipley-Wilson rotameter was utilized to measure mixture made alkaline and extracted with ether. Drying the rate of blood flow through the femoral artery. Other and removal of the ether and distillation of the residue procedures which were employed to evaluate the effect gives 2-(B-ethylthiopropyl)-6-methyl l,2,3,4-tetrahydro- 15 of the tetrahydroisoquinoline are set forth in the examples. isoquinoline. Elemental and infrared analysis confirms the Preliminary toxicity studies on 2-(3-ethylsulfinylprostructure. pyl)-l,2,3,4-tetrahydroisoquinoline were conducted fol- To an ice cold solution of 0.1 mole of the 2-(3-ethylthiolowing the usual, well defined, and standardized procepropyl)-6-methyl-l,2,3,4tetrahydroisoquinoline and 6 ml. dures as described in the phamphlet Appraisal of the of glacial acetic acid in 50 ml. of acetonitrile is added, 29 Safety of Chemicals in Foods, Drugs and Cosmetics," dropwise with stirring, a solution of 19 grams of compublished in 1959 by the association of Food and Drug mercial 40% peracetic acid (0.1 mole) in milliliters of Officials in the United States. (Hogan, Acute Toxicity," acetonitrile. The reaction mixture is stirred at room tempage 17; Fitzhugh, Subacute Toxicity," page 26; and perature for one hour, poured into 150 ml. of water, made Fitzhugh, C Oral Toxicity. page 36). Sixty day basic with dilute aqueous ammonia and extracted with 5 subacute toxicity tests in Wistar rats (15, 50 and 150 ether. The ether solution is washed with dilute potassium mgjkg. of body weight per day) and Beagle dogs (10, carbonate solution, dried and treated with ethereal hydro- 30, 60 an 90 mgJkg. of body weight per day) indicated gen chloride. The resulting precipitate is recrystallized Significant biochemical I s l gical viden e of from isopropyl alcohol to yield 2-(3-ethylsulfinylprop l)- toxicity. The composition was administered to the dogs 6 methyl 1,2,3,4-tehrahydroisoquinoline hydrochloride. rally in p ules, once daily, five days per week. The Elemental and infrared analysis confirms the structur rats received the same composition orally in drinking water seven days per week. EXAMPLES 24-31 The effective dosage of the compounds of this inven- In the following examples the analogous compounds tion depends upon the indiivdual characteristics of each are prepared as indicated. The methods employed are case. In general, however, it has been observed that an the same as those set forth in the preceding example. The effective concentration of the tetrahydroisoquinolines will starting materials and final products are set forth in Table usually range from about 0.10 to about 75 milligrams per II below: kilogram of body weight of the warm blooded animal.

TABLE II Methodr En. Compound Starting material Examplia 24 2-(3-ethylthioprnpyl)4-methyl-l,2,3,t-tetrahydrolsoqulnollne 4-methy1-12,3,4-tetmhydrolsoquinollne 2 25 2-(3-ethy1sulfinylpropyl)-4-methyl-l.2,3,4tetrahydrolsoqulnoline. Compound of Example24 2 2B. Hit-methylthlopropyl)-6-methoxy-l,2,3,4-tetrahydroisoquinoline 6-methoqy-l,2,3,4-tetrahydroisoquinoline 2 27 2-[3-methylsulfonylpropyl)-6-methoxy-l,2,3,4-tetrahydroisoquinoll Compound of Example 20 4 25 2-(3-propylthlopropyl)-7ehloro-l,2,3.4-tetrahydrolsoqulnoline. 7-chloro-l,2,3,4-tet.rahydroisoquinoline. 23 29 2-(3-propylsulfinylpropyl)-7-chloro-l2,3,4-tetrahydroisoquinoline. Compound of ExampleZS 4 30. 2-(It-ethylthiopropyl)-6-trifluoromethyl-l,2,3,4-tetrahydrolsoquinoline fi-trlfluoromethyl-l,2,3,4-tetrahydrolsoqulnollne.. 23 31 2-(3-ethylsulfinylpropyl)-fl trlfluoromethyl-l,2,3,4-tetrshydroisoqulnollne Compound 01 Exampleao 4 The manner of using the invention sought to be pat- A preferred range is from about 0.25 to about 50 milliented in its process aspect will now be described. Quite unexpectedly, it has been discovered that the tangible embodiments of this invention exhibit favorable cardiovascular effects in warm blooded animals. It has been observed that these compositions are useful as therapeutic agents for increasing systolic blood pressure, with little or no concurrent increase in diastolic blood pressure. Hence, the compositions are useful as valuable therapeutic agents in the alleviation and control of low systolic blood pressure as would be associated with shock and other disorders. Additionally, it has been observed that the compositions of this invention are particularly unique in that while the blood pressure is increased there is no concurrent decrease in blood flow in the peripheral vascular system. In fact, an increase in blood flow rate in the I peripheral vascular system has been observed when the tetrahydroisoquinoline was administered.

Various well known procedures were carried out to ascertain the cardiovascular effect of 2-(3-ethylsulfinylpropyl)-l,2,3,4-tetrahydroisoquinoline. In the preliminary tests 2-(3ethylsulfonylpropyl)-l,2,3,4-tetrahydroisoquinoline was administered to anesthetized and unanesthetized dogs as the hydrochloride.

In the case of unanesthetized dogs, the systolic blood pressure was measured indirectly by using a tail cuff grams per kilogram of body weight. The tetrahydroisoquinolines can be formulated into capsules, tablets, injectable solutions, and the like. Tablets and capsules can be formulated with the usual ingredients and excipients such as starch, methylcellulose, natural gums, dibasic calcium phosphate, lubricants, dispersing agents and the like.

In some instances it may be preferred to administer the tetrahydroisoquinolines by infusion, such as with plasma, at a constant rate over an extended period of time. In such cases, the effective concentration can be adjusted to provide the desired dosage levels.

The following examples set forth the manner of using the tetrahydroisoquinolines of this invention for increasing the blood pressure in warm blooded animals.

EXAMPLE 22 Effect of tetrahydroisoquinolines on systolic blood pressure (a) An unanesthetized dog having a control blood pressure of /170 was injected intravenously with 0.5 mgjkg. of 2-( 3- ethylsulfinylpropy)-l,2,3,4-tetrahydroisoquinoline hydrochloride and observed for one hour. Immediately following the injection, the person holding the dog noted a forceful pounding of the heart. This was accompanied by an increase in heart rate from a control 13 level of 126 to 168. The heart rate then returned to the control level of 126 by the end of thirty minutes. The systolic blood pressure immediately increased from 180 to 220-230 and had almost returned to control level by the end of one hour. No increases in diastolic pressure were observed.

(b) A second unanesthetized dog which was very calm and had a control blood pressure of 120/70 which changed to 150/66 thirty minutes after intravenous administration of 1 mg./kg. of 2-(3-ethylsulfinylpropyl)-l,2,3,4-tetrahydroisoquinoline hydrochloride. Heart rate increased from 72 to 100. Little or no gross stimulation occurred. On another day this same dog was injected intravenously with 0.5 mg./kg. of 2-(3 ethylsulfinylpropyl) 1,2,3,4- tetrahydroisoquinoline hydrochloride. From a control pressure of 122/60 the pressure increased to 130/65 7-l0 minutes after injection. A maximal increase to 145/73 occurred 43 minutes after injection. One and one-half hours after injection the pressure was almost back to control levels.

EXAMPLE 33 Effect of tetrahydroisoquinolines on cardiac output The effect of 2-(3-ethylsulfinylpropyl) l,2,3,4 tetrahydroisoquinoline on cardiac output was determined in a pentobarbitalized dog. The dosage was 1 nag/kg. of body weight administered intravenously as the hydrochloride. The cardiac output was obtained by the dyedilution method utilizing Cardio-Green dye and a Waters Densitometer. Dye injections were made through a catheter inserted through the right jugular vein and positioned near, or in the right atrium. Arterial sampling for dye was from the left carotid artery. The results of this experiment is given in Table III. Each value in the table represents data from one dye-dilution curve. The values for controls are averages of the number in parentheses and were taken during the few minutes immediately preceding administration of the tetrahydroisoquinoline.

TABLE III Mean Total Cardiac arterial perlph- Heart output, blood er rate, Stroke liters] pressure, resistbea volume, min. mm. g once 1 min ml.

1 Pressure (mm. Hg) cardiac output (ml/see).

EXAMPLE 34 Effect of tetrahydroisoquinolines on blood flow The Shipley-Wilson rotameter was utilized to measure the rate of blood flow through the femoral artery in the subject anesthetized dogs. Injection of 1 mg. of 2-(3-ethylsulfinylpropyl)-l,2,3,4-tetrahydroisoquinoline hydrochloride into the tubing leading directly to the femoral artery resulted in an increase in flow of 1 to 2 minutes duration. This increased flow was apparently due to vasodilation since the blood pressure (recorded from the same tubing leading directly to the artery) was not increased. In two anesthetized dogs femoral blood flow was recorded and 0.5 to 1.0 mg./kg. of the same tetrahydroisoquinoline hydrochloride was injected intravenously. Increases in flow of 3 to 5 minutes duration were observed. These changes were not due to any increase in blood pressure. In one of these dogs an additional intravenous injection of mg./ kg. of the tetrahydroisoquinoline caused evidence of prolonged vasodilation.

Simple substituents on the tetrahydroisoquinoline moiety of the compounds of the present invention do not adversely affect the pharmacological properties thereof, and are to be regarded as the full equivalents of the compounds of the invention wherein the tetrahydroisoquinoline moiety is unsubstituted. For example, the molecule may also contain substituents wherein R or R" groups are other than hydrogen. Such additions to the molecular structure of the inventive concept herein described are, therefore, equivalents of the subject matter sought to be patented.

As previously indicated, the aforementioned general formula defines the compounds of the present invention as the free base form thereof. Inasmuch as the physical embodiments of the inventive concept have pharmacological utility, for such use the compounds will usually be administered in the form of their pharmaceutically acceptable acid addition salts, these salts are the full equivalents of the free base forms thereof. The acid addition salts can be prepared by reacting the corresponding free bases in a conventional manner with an inorganic acid such as hydrochloric, hydrobromic, sulfuric and phosphoric; or an organic acid, such as methanesulfonic, ethanesulfonic, ethanedisulfonic, cyclohexylsulfamic, formic maleic, citric, tartaric and tannic acids. The compounds can also be administered in the form of their quarternary ammonium salts formed b the reaction with a lower alkyl halide.

In addition to their use as the essential active ingredient in pharmaceutical formulations, the novel compositions of this invention can be employed in a variety of other fields. For example, the tetrahydroisoquinoline compounds of this invention are useful as intermediates in the synthesis of other chemical compounds.

What is claimed is:

1. A compound selected from the group consisting of tetrahydroisoquinolines having the formula:

n RI wherein A is an alkylene group having at least one and not more than seven carbon atoms; X is selected from the group consisting of sulfinyl or sulfonyl; R is an alkyl group having at least one and not more than seven carbon atoms; R is selected from the group consisting of hydrogen or lower primary or secondary alkyl groups; R" is selected from the group consisting of lower alkyl [or], lower alkoxy, halo and :rifluoromethyl groups; n has a value of zero through 2; provided that when R" is trifluoromelhyl, than n has value 2; and the pharmaceutically acceptable acid addition salts of said tetrahydroisoquinolines.

2. The composition of claim 1 wherein R is hydrogen, n is zero and AX-R is the alkylsulfinylalkyl group. 3. The composition of claim 1 wherein R is hydrogen, n is zero and -A--X-R is the alkylsulfonylalkyl group. 4. The composition of claim 1 wherein AXR is selected from the group consisting of alkylsulfinylpropyl and alkylsulfonylpropy 5. The composition of claim 1 wherein R is hydrogen, n is zero and A-XR is the alkylsulfinylpropyl group. 6. The composition of claim 1 wherein R is hydrogen, n is zero and A-X-R is the alkylsulfonylpropyl group.

7. 2 (3 ethylsuliinylpropyl) l,2,3,4 tetrahydroisoquinoline.

ethylsulfonylpropyl) 1,2,3,4 tetrahydroisoquinoline.

(References on following page) patent.

References Cited The following references, cited by the Examiner, are of record in the patented file of this patent or the original UNITED STATES PATENTS Shen 260-283 S Thirtle 260287 X Cusil 260288 Bloom 260-237 X Haack et a] 260--286 X Schmidt et al 260-283 X Yonan 260-233 Brown 260247.5

Robinson 260-288 1 6 OTHER REFERENCES Gray et aL, Chem. Abstn, vol. 7], col. 81213:), abstracting German 1, 806, 900.

Chawla et aL, Chem. Abstn, vol. 72, col. 132240Z 5 (1970).

DONALD G. DAUS, Primary Examiner US. Cl. X.R.

10 260-286 A, 283 SA, 286 288 R, 289 R, 287 R, 283

3 3 33 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No- He. 28,03 4 Dated un 4, 197

Inventor(s) A1 lan Poe Gray It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

f" Tn column 1 4 rewrite lines 52 through 59 f l "'I -;,1,1,0ms L R 31 1:; selected from the group consisting of hydromn or lower primary or secondary alkyl groups; R" is selected from the group consisting of lower silky/nor] lower alkoxy palo QQQ jil QliliIiDlfiGtQf/i groups; Q has a value of zero through 2; lz srided that when R" is trifluorornethyl, then n has a value of and the pharmaceutically acceptable acid [solution] addition 1 of said tetrahydroisoquinolines. W

and sealed this 17th day of September 1974.

(SEAL) Attest:

MCCOY N. GIBSON JR. C. MARSHALL DANN Attesting Officer Commissioner of Patents 

